Molecular modeling studies of quinoline derivatives as VEGFR-2 tyrosine kinase inhibitors using pharmacophore based 3D QSAR and docking approach

Pharmacophore modeling studies were undertaken for a series of quinoline derivatives as VEGFR-2 tyrosine kinase inhibitors. A five-point pharmacophore with two hydrogen bond acceptors (A), one hydrogen bond donor (D), and two aromatic rings (R) as pharmacophore features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of r 2  = 0.8621 for training set compounds. The model generated showed excellent predictive power, with a correlation coefficient of q 2  = 0.6943 and for a test set of compounds. Furthermore, the structure–activity relationships of quinoline derivatives as VEGFR-2 tyrosine kinase inhibitors were elucidated and the activity differences between them discussed. Docking studies were also carried out wherein active and inactive compounds were docked into the active site of the VEGFR-2 crystal structure to analyze drug-receptor interactions. Further we analyzed all the compounds for Lipinski’s rule of five to evaluate drug likeness and established in silico ADME parameters using QikProp. The results provide insights that will aid the optimization of these classes of VEGFR-2 inhibitors for better activity, and may prove helpful for further lead optimization and virtual screening.